The ubiquity of cortico-cortical feedback connections argues strongly for their importance, and theoreticians routinely make use of them in models of cortical function. Despite this, next to nothing is known about their function. The existing studies in which feedback has been manipulated have been performed in anesthetized animals, and our preliminary studies in alert animals reveal fundamentally different results. We thus propose to embark on a new exploration of the function of cortico-cortical feedback in alert animals, making use of chronically implanted cryoloops and multi-electrode arrays. We will use these devices to reversibly inactivate a portion of the 2nd and 3rd visual areas (V2/V3) within the lunate sulcus-corresponding to the inferior, contralateral quadrant of visual space within approximately 15 degrees of the fovea-while recording the visually evoked responses of neurons in striate cortex (V1). We will systematically explore the extent to which feedback exerts specific influences, such as those in theoretical proposals for "predictive encoding," as opposed to a more generic form of gain control. In addition to testing the specificity of cortico-cortical feedback, we will use our manipulations to probe the mechanisms of center-surround opponency and to determine to what extent local, intrinsic connections can subserve various receptive field properties. Our studies will shed light on the basic mechanisms of cortical function. PUBLIC HEALTH RELEVANCE: A number of human mental diseases are believed to be, fundamentally, developmental disorders that result in abnormal cortical connectivity. The autism spectrum disorders are but one important example (Minshew &Williams 2007) where the principle functional deficits appear to concern integration of information and these have been linked to abnormalities in corticocortical connectivity as assessed by both functional and anatomical magnetic resonance imaging (Just et al. 2007, Herbert et al. 2004). Schizophrenia is another neurodevelopmental disorder in which an impairment of feedback processing has been specifically implicated (Dima et al. 2010, Kemner et al. 2009, Williams et al. 2009), and, given that we know very little about the various roles played by feedback connections, the insights gained from the proposed studies will aid efforts to piece together the pathophysiology of cortical mis-wiring syndromes.